Trials of GDNF in Parkinson’s disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. [ 18 F]DOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.

Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [ 18 F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7 ± 20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6 ± 23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI:-13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week

The goals of the Earth Biogenome Project—to sequence the genomes of all eukaryotic life on earth—are as daunting as they are ambitious. The Darwin Tree of Life Project was founded to demonstrate the credibility of these goals and to deliver at-scale genome sequences of unprecedented quality for a biogeographic region: the archipelago of islands that constitute Britain and Ireland. The Darwin Tree of Life Project is a collaboration between biodiversity organizations (museums, botanical gardens, and biodiversity institutes) and genomics institutes. Together, we have built a workflow that collects specimens from the field, robustly identifies them, performs sequencing, generates high-quality, curated assemblies, and releases these openly for the global community to use to build future science and conservation efforts.

Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems.

The analysis of interaction networks across spatial environmental gradients is a powerful approach to investigate the responses of communities to global change. Using a combination of DNA metabarcoding and traditional molecular methods we built bipartite Drosophila-parasitoid food webs from six Australian rainforest sites across gradients spanning 850 m in elevation and 5° Celsius in mean temperature. Our cost-effective hierarchical approach to network reconstruction separated the determination of host frequencies from the detection and quantification of interactions. The food webs comprised 5-9 host and 5-11 parasitoid species at each site, and showed a lower incidence of parasitism at high elevation. Despite considerable turnover in the relative abundance of host Drosophila species, and contrary to some previous results, fundamental metrics of network structure including nestedness and specialisation did not change significantly with elevation. Advances in community ecology depend on data from a combination of methodological approaches. It is therefore especially valuable to develop model study systems for sets of closely-interacting species that are diverse enough to be representative, yet still amenable to field and laboratory experiments.

Abstract. 1. The choice of metrics comparing pristine and disturbed habitats may not be straightforward. We examined the results of a study in Gabon including 21 arthropod focal taxa representing 16 855 individuals separated into 1534 morphospecies. Replication included the understorey of 12 sites representing four stages of land use after logging (old and young forests, savanna and gardens), surveyed for 1 year using three sampling methods.2. For all focal taxa, we calculated a suite of 13 metrics accounting for the intensity of faunal changes between habitats, namely: abundance; observed, rarefied and estimated species richness; proportion of rare species; additive diversity partitioning; evenness of assemblages; higher taxonomic composition; species turnover; ordination scores of multivariate analyses; nestedness; proportion of site-specific species and ratios of functional guilds.3. Most metrics showed large differences between forests and non-forest habitats, but were not equally discriminating for particular taxa. Despite higher taxonomic groups being present in most habitats, many insect species were site or habitat specific. There was little evidence that the disturbance gradient represented a series of impoverished habitats derived from older forests. Rather, entire suites of species were being replaced as habitats were modified.4. Metrics based on species identity had a high sensitivity to disturbance, whereas measurements describing community structure were less discriminating in this regard. We recommend using metrics based on abundance, estimated species richness, species turnover estimated by multivariate analyses and guild structure, to avoid misleading interpretations that may result from comparisons of species richness alone. Key words. Additive diversity partitioning, biodiversity, nestedness, parataxonomist, species loss.

OBJECTIVEThe pan–histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.METHODSThe authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White–Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED.RESULTSThere were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively.CONCLUSIONSCED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.

Logging and habitat fragmentation impact tropical forest ecosystems in numerous ways, perhaps the most striking of which is by altering the temperature, humidity, and light environment of the forest-its microclimate. Because local-scale microclimatic conditions directly influence the physiology, demography and behavior of most species, many of the impacts of land-use intensification on the biodiversity and ecosystem functioning of tropical forests have been attributed to changes in microclimate. However, the actual pathways through which altered microclimatic conditions reshape the ecology of these human-modified ecosystems remain largely unexplored. To bridge this knowledge gap, here we outline an agenda for future microclimate research in human-modified tropical ecosystems. We focus specifically on three main themes: the role of microclimate in shaping (i) species distributions, (ii) species interactions, and (iii) ecosystem functioning in tropical forests. In doing so we aim to highlight how a renewed focus on microclimate can help us not only better understand the ecology of human-modified tropical ecosystems, but also guide efforts to manage and protect them.